FIRST-LINE MANAGEMENT OF A SYMPTOMATIC LYMPHATIC LEAK
CASE 1: A newborn female with Noonan syndrome is
admitted to the neonatal ICU for persistent abdominal ascites. Exam
demonstrates diffuse soft tissue edema, a moderately distended abdomen,
and stable vitals. Diagnostic paracentesis confirms the fluid is chylous
and peripheral laboratory evaluation is notable for hypoalbuminemia,
hypogammaglobulinemia and lymphocytopenia. MR lymphangiography
identifies areas of likely congenital intestinal lymphangiectasia.
Treatment recommendations include immediate transition to a medium-chain
triglyceride diet, IV albumin repletion, and serial abdominal ultrasound
surveillance to monitor rate of ascites reaccumulation. In the following
4 weeks, only one additional therapeutic paracentesis is required
indicating a “low-flow” rate lymphatic leak, and the frequency of
albumin replacement greatly decreases as peripheral edema resolves.
After 8 weeks on a medium-chain triglyceride formula (Portagen), the fat
and caloric content of her diet is slowly liberalized without further
evidence of ascites or edema.
Multidisciplinary management of a symptomatic lymphatic leak centers
around respiratory support, volume repletion, diet augmentation and
minimally invasive attempts to treat the source of a lymphatic leak. The
goal of first-line management is to encourage spontaneous and timely
closure of leaking lymphatic vessels.
If the clinical scenario allows, a period of observation and medical
support is indicated for both premature and term infants presenting with
chylous leaks. In some instances, chylous leaks are temporary.
Postnatally, lymphovenous communications can be established through
collateral channels or lymph nodes (mediastinal, lumbar, renal, or
hepatic) allowing chyle to regain access to the general circulation.
Development of alternative lymphatic flow can take weeks to months.
Patience must be incorporated into the care of congenital chylothorax
and chylous ascites. Limiting frequent adjustments to treatment regimen
is helpful so as to not confound the ability to interpret response to
interventions.
Antenatal interventions for congenital chylous collections include
serial ultrasounds, intrauterine interventions such as thoracoamniotic
shunt, and rarely, intrauterine chemical pleurodesis[17].
Thoracoamniotic shunting for congenital chylothorax and reversal of
hydrops significantly improves survival; prematurity portends a worse
prognosis and increased mortality.[17] The longer the interval
between thoracomaniotic shunting for congenital chylothorax and
delivery, the more likely the reversal of hydrops and neonatal
survival.[17]
Low-flow lymphatic leaks (< 500 ml/day in adults, or roughly
< 20 ml/kg/day in children) may close spontaneously and/or
respond to supportive care medical management. High flow lymphatic leaks
(> 1 L/day in adults, or roughly > 20
ml/kg/day in children) tend to require more aggressive therapy including
surgical or interventional procedures to reduce morbidity and
mortality.[18] (Figure 3). Maintaining a drain until the
patient is tolerating a full diet allows for monitoring of continued
leak. Alternatively, serial abdominal or chest ultrasonography are
utilized when necessary to monitor reaccumulation.
Drainage: In symptomatic chylous effusion, intermittent
aspiration of fluid and/or placement of thoracostomy tube for continuous
drainage can be necessary to improve symptoms, allow for better lung
expansion, and decrease the size of potential pleural space to help seal
the lymphatic leak. Despite drainage, some lymphatic leaks persist,
leading to the need for chronic drainage. Mechanical ventilation is
sometimes necessary. Similarly, in symptomatic chylous ascites,
intermittent aspiration of fluid and/or placement of a peritoneal drain
for continuous drainage may be indicated to decrease abdominal
distention and improve lung expansion. Thoracentesis or peritoneal fluid
aspiration allows for fluid analysis to confirm the fluid is lymphatic
in origin (Table 2) .
Nutritional Management: Goals of nutritional supportive care
include decrease chylous production and accumulation of effusion or
ascites, maintenance of adequate nutrition and electrolytes, and protein
repletion. A symptomatic chylous effusion or ascites should be monitored
for twenty-four hours to establish a baseline rate of lymphatic leak.
Daily weights should be documented to monitor for shifts in fluid
balance.
Patients who demonstrate a “low-flow” rate (< 20 ml/kg/day)
of lymphatic leak may benefit from a trial off long-chain-fats (LCF) to
a medium-chain-triglyceride (MCT) based formula. Long chain fats (LCF)
make up most of our dietary fat. Their digestion is complex and involves
both the gastrointestinal and lymphatic systems. Chyle from intestines
is a protein rich fluid - returning between one-fourth to one-half of
plasma protein in circulation to the body. LCFs are ingested and
released as micelles with fat in the small bowel. Here, the micelles
interact with pancreatic lipase, breaking down the LCF. Micelles
transport fatty acids to intestinal villi where they are absorbed.
Medium chain triglycerides (MCT), however, are easily absorbed across
the small intestine into the portal system without requiring transport
into the lymphatic system. Because of this, a diet including MCT
products should not increase the production of lymphatic fluid. Slowly,
over the course of weeks, a low-fat diet associated with MCT may resolve
clinical and biochemical complications. If drain output does not
decrease after 1-2 weeks on MCT diet, transitioning to complete gut rest
with total parenteral nutrition with or without octreotide as an adjunct
should be considered.
Formulas that contain high levels of MCT include Portagen, Progestimil,
and Enfaport (Table 3) . Newborns whose enteral intake consists
exclusively of MCT containing formulas are at risk for developing
essential fatty acid (EFA) deficiency. A fatty acid profile and
fat-soluble vitamins (Vitamin A, D, E, K) should be monitored in these
patients after 1-2 weeks of initiating an MCT based formula and consider
adding an EFA supplement to the diet. EFA deficiency can develop within
the first few weeks of a lymphatic leak and presents with skin rashes,
impaired wound healing, thrombocytopenia and growth delays. Lipids are
an essential part of development of the nervous system; the
developmental impact limiting lipid intake may impact early brain
growth. As a lymphatic leak improves, fatty acid profile should be
monitored every 3 months until normalized and then every 6 months after.
In patients with a “high-flow” rate (> 20ml/kg/day) of
lymphatic leak and those who are refractory to MCT formula, more
aggressive nutritional restriction is indicated. Cessation of all
enteral nutrition to reduce the production of chyle driven by dietary
fat intake may be indicated. Total parenteral nutrition (TPN) with
intravenous lipids is initiated to replete caloric and electrolyte
deficiencies and improve fluid balance. Intravenous lipids are delivered
directly into the blood stream, do not travel through the lymphatic
system and are not contraindicated in the treatment of high-flow
lymphatic leak.
Laboratory monitoring: With a symptomatic lymphatic leak,
electrolyte and organ function should be evaluated with a complete
metabolic panel. Protein loss can be estimated by serum albumin and IgG
level. A complete blood count helps monitor progressive lymphopenia. The
frequency of laboratory monitoring is relative to the rate of lymphatic
loss. Whereas high-flow lymphatic loss may require metabolic panel
monitoring multiple times daily, low-flow lymphatic loss often only
requires once daily monitoring and frequency can be liberalized as
symptoms resolve to spare cumulative blood loss.
Albumin repletion: The efficacy of albumin replacement, in
general, has been controversial in critical care medicine. Although not
a direct therapy for lymphatic leak, repletion of albumin is often
performed when disease is complicated by serous effusions or symptomatic
limb edema (third spacing). Albumin provides an increase in
intravascular oncotic pressure and causes mobilization of fluids from
interstitial into intravascular space. For effusions or ascites with
hypoalbuminemia, 25% albumin (250 mg/ml) can be given at 1g/kg/dose
infused over 2 to 3 hours. The dose can be repeated up to three times
per day until the serum albumin is > 2.5 g/dL; maximum dose
of 25 g/dose.[19] Side effects of an albumin infusion may include
hypertension, tachycardia, fever, chills, rash, nausea and vomiting.
Serial albumin infusions intravenously may reduce edema, but the impact
is often transient.
Octreotide: Octreotide is a synthetic somatostatin analogue
commonly used to treat secretory diarrhea, esophageal varices, and
post-gastrectomy dumping syndrome. The mechanism of action of octreotide
involves reduced splanchnic blood flow, portal pressure, and intestinal
absorption of fats. Additionally, octreotide decreases gut motility and
splanchnic lymphatic production. In the setting of high-flow or
refractory lymphatic leak evidence supports the use of octreotide to
reduce the rate of lymphatic leak in both congenital and acquired
chylous effusion and ascites. An initial dose is commonly 1-2
mcg/kg/hour as a continuous intravenous infusion, titrating up to a
clinical response with a median maximum dose of 10 mcg/kg/hour. Although
octreotide can be delivered subcutaneously, there is greater evidence of
efficacy in children and neonates when given intravenously. Duration of
therapy commonly ranges from 7 to 14 days.[20] Congenital lymphatic
leak tends to require higher doses and a longer duration of therapy
compared to acquired lymphatic leak. Side effects include bradycardia,
hypertension, worsening of underlying pulmonary hypertension,
hyperglycemia, and headache. Octreotide may be considered immediately in
patients with high-flow output with symptomatic electrolyte and protein
losses, or in patients who have failed an NPO trial of 1-2 weeks.
IgG repletion: Although not a direct therapy for lymphatic leak,
adjuvant IgG repletion may be necessary. IgG repletion via intravenous
immunoglobulin (IVIG) should be reserved for patients actively fighting
infectious complications. In this case, low dose infusions of
~400mg/kg can be given to maintain a minimal physiologic
IgG. Transfused immunoglobulins are quickly depleted by continuous
lymphatic leak making it difficult to maintain higher serum
concentrations. In the patient without active infections, serial IVIG
infusions given to improve the serum IgG value risk the introduction of
a considerable fluid burden that may cause more harm to fluid balance
than active benefit.
Fever management: Fluid within an effusion or ascites is at risk
of becoming infected. Providers should have a low threshold to evaluate
and treat febrile patients with a lymphatic leak. Consider oral
antibiotic course for fever without a source and consider intravenous
broad coverage antibiotics for fever with culture positive focal source.
In the setting of chylous ascites, gram-negative coverage, such as a
third-generation cephalosporin is generally recommended. Although the
literature lacks recommendations for the initiation of Pneumocystis
jiroveci pneumonia (PJP) prophylaxis in the setting of lymphatic leak,
we have applied a general recommendation often used for patients with
immunodeficiency; PJP prophylaxis is considered when the absolute
lymphocyte count is < 500 cells/µL, or, if available, when the
CD4+ T cell lymphocyte count is < 200 cells/µL.